The continuing goals of the proposed research remain to constantly discover and develop novel anti-HIV compounds from plant-derived natural products and their analogs. A distinctive and valuable collaboration between academia [Dr. K.H. Lee, UNC] and Panacos Pharmaceuticals, Inc continues to discover and develop novel small molecule HIV inhibitors from natural products and their synthetic analogs. The considerable progress includes the discovery of numerous new leads, which could serve as novel templates for drug design of potential clinical trials anti-AIDS drug candidates. Dimethyl succinyl betulinic acid (DSB) is one of the most promising compounds resulting from the collaboration. DSB is the first in a completely new class of HIV drug candidates called "maturation inhibitors". This mechanism of action is completely distinct from other inhibitors that have been described in the past. Various analogs of the dicamphanoyl khellactone (DCK) family are also being tested for their development potential. These compounds act by inhibiting reverse transcription, but by a mechanism that appears to differ from currently available non-nucleoside RT inhibitors. Their value as potential drug candidates continues to be assessed. Future plans include: 1. Isolation studies - Bioactivity-directed fractionation and isolation (BDFI) and characterization of the HIV inhibitors from active plant extracts, including extracts of 66 previously unexplored plant species. 2. Analog syntheses - Further syntheses of new water-soluble DCK analogs, including DCP and their thio bio-isosteres, to enhance bioavailability will be a major focus, in addition to structural modification of other new leads discovered in this project for better pharmacological profiles. 3. Antiviral spectrum assays -- The isolated compounds or synthesized analogs that exhibit anti-HIV activity against HIV replication in H9 lymphocytes will be tested against a panel of HIV-1 primary isolates representing group M, subtype A to G, and groups N and O obtained from the NIH/NIAID reagent program, as well as against drug resistant virus isolates. Promising new leads will also be submitted to NIH for further evaluation against other HIV viruses. 4. Metabolism studies -- In vitro metabolism studies using rat and human liver microsomes, as well as recombinant enzymes, will be carried out in order to assess development potential of active compounds. 5. Mechanism of action -Further elucidation of the precise molecular targets of promising compounds will continue. 6. Preclinical and clinical development- After approval of an IND for DSB (PA-457), which was filed in December 2003, the Phase I clinical trials are scheduled to begin in early 2004. The goal is to develop an orally active drug with a novel mechanism of action that will add to the treatment options for HIV/AIDS.